Profiles of "manic" symptoms in bipolar I, bipolar II and major depressive disorders

BACKGROUND: Classical authors such as Kraepelin, as well as the emerging literature during the past decade, indicate that manic-like signs and symptoms are present to a variable degree in all mood disorders. Current nosography does not differentiate between them and only the number of symptoms or severity is used for classification. This is particularly true for mania and hypomania. This paper will analyze the patterns of manic symptoms in bipolar I (BP-I), bipolar II (BP-II) and major depressive disorders (MDD), to test the hypothesis that mania and hypomania have different profiles, and ascertain which excitatory manic phenomena do occur in unipolar MDD. METHODS: Six hundred and fifty-two inpatients (158 BP-I, 122 BP-II and 372 MDD) were assessed using the operational criteria for psychotic illness checklist (OPCRIT) [Arch. Gen. Psychiatry 48 (1991) 764] with a lifetime perspective. Manic or hypomanic symptoms were investigated and compared between BP-I, BP-II and MDD. RESULTS: When compared with BP-II, BP-I disorder had a higher prevalence of reckless activity, distractibility, psychomotor agitation, irritable mood and increased self-esteem. These five symptoms correctly classified 82.8% of BP-I and 80.1% of BP-II patients. One or two manic symptoms were observed in more than 30% of major depressive patients; psychomotor agitation was the most frequent manifestations present in 18% of the MDD group. LIMITATIONS: We did not control for severity of symptoms, nor for neuroleptic use that could produce akathisia. CONCLUSIONS: This study suggests that mania and hypomania can be differentiated in their symptom profiles, and highlights the presence of few manic symptoms, particularly psychomotor agitation, in MDD. From the standpoint of number of manic signs and symptoms, controlling for psychomotor agitation did not substantially change the predictive power of the remaining manic symptoms. Given that excitatory manic signs and symptoms are present to a decreasing degree in BP-I, BP-II and MDD, these disorders can be proposed to lie along a dimensional model. Overall, these data are compatible with the concept of a bipolar spectrum, whereby each of the affective subtypes requires specific genetic factors.     

The dark side of bipolarity: detecting bipolar depression in its pleomorphic expressions

The depressive expressions of bipolar disorders have long been neglected. Current data, from both clinical and epidemiologic studies, indicate that such expressions far exceed the manic forms in both cross-section and during follow-up course. Thus, mania occurs in 1% of the population at large; bipolar depression afflicts at least 5 times more people. Much of the new literature on this subject has emphasized its high prevalence, morbidity, and mortality. There has been relatively less attention paid to the phenomenology of bipolar depression as it presents clinically. This special issue (volume 84/2-3, 2005) is devoted to a systematic data-based in-depth examination of the different clinical expressions of bipolar depression including, among others, retarded depression, agitated and/or activated depression, mood-labile depression, irritable-hostile depression, atypical depression, anxious depression, depressive mixed state, and resistant depression. Both bipolar I (BP-I), and the more prevalent yet relatively understudied bipolar II (BP-II), are covered. We trust that this extensive coverage of the "darker" side of bipolarity will set the stage for a much needed renaissance in its complex phenotypic expressions-and its delimitation from unipolar depression (UP). The phenomenology of BP-I depression ranges from depressive stupor to agitated psychosis, whereas UP depression expresses itself in psychic anxiety, and insomnia, as well as retardation. BP-II compared with UP is more likely to have atypical features, mood lability, hostility, activation, biographical instability, multiple anxiety comorbidities, suicidal tendencies, and to be rated as less "objectively" depressed. These findings are complex and do not fully agree with the conventional characterization of BP as retarded and UP as anxious and agitated. The inconsistency between the conventional and the phenomenology described herein is largely due to depressive mixed states, which tend to destabilize BP-II, and may account for the "contradictory" relationships of affect, sleep, drive, and psychomotor activity in mood disorders.     

Irritable-hostile depression: further validation as a bipolar depressive mixed state

BACKGROUND: "Hostile depression" has unofficially long been described as a depressive subtype, but since DSM-III, the affect has been made a defining characteristic of borderline personality disorder. The related affect of irritability in DSM-IV-TR subsumes various hostile nuances and is included in the stem question for mood disorders--especially for hypomanic episodes; in children, it is nonetheless a sign of depression. Then, there is the unofficial more general concept of depression with anger attacks, until recently ostensibly a "unipolar" (UP) disorder. A veritable tower of Babel indeed. In the present analyses, our aim was to extend previous research on irritable-hostile depression to more specific parameters of bipolarity and depressive mixed state (DMX). METHODS: Consecutive 348 bipolar-II (BP-II) and 254 unipolar (UP) major depressive disorder (MDD) outpatients (off psychoactive agents, including substances of abuse), were interviewed with the Structured Clinical Interview for DSM-IV, the Hypomania Interview Guide, and the Family History Screen. Borderline personality, a confounding variable, rare in the FB setting, was excluded. Irritability was defined according to DSM-IV-TR, which includes various features of hostility and anger. Depressive mixed state (DMX) was defined as a major depressive episode (MDE) plus three or more concurrent intradepressive hypomanic symptoms, whether it occurred in BP-II or MDD. RESULTS: MDE with irritability was present in 59.7% (208/348) of BP-II and in 37.4% (95/254) of MDD (p=0.0000). In BP-II, MDE with, versus MDE without, irritability had significantly younger index age, higher rates of axis I comorbidity, atypical depressive features, and DMX. Upon logistic regression, we found a significant independent association between BP-II MDE with irritability and DMX. In UP, MDE with, versus without, irritability had significantly younger age and age at onset, higher rates of atypical depression, DMX, and bipolar family history. Logistic regression revealed a significant independent association between MDE with irritability and DMX. Given that we had excluded patients with borderline personality, the high prevalence of irritable-hostile depressives in this outpatient population means that hostility cannot be considered the signature of that personality. Factor analysis revealed independent "psychomotor activation" and "irritability-mental activation" factors. Odds ratios of irritability for DMX were highest in the "UP" MDD group (=12.2); for predicting DMX, irritability had the best psychometric profile of sensitivity of 66.3% and a specificity of 86.1% for this group as well. LIMITATION: We did not use specific instruments to measure irritable, hostile, and angry affects. CONCLUSIONS: These analyses show that irritable-hostile depression is distinct from agitated depression. Whether arising from a BP-II or MDD baseline, irritable-hostile depression emerges as a valid entity with strong links to external bipolar validators, such as bipolar family history. Irritable-hostile phenomenology in depression appears to be a strong clinical marker for a DMX. Irritable-hostile depression as a variant of DMX deserves the benefit of what seems to work best in practice, i.e., anticonvulsant mood stabilizers and/or atypical antipsychotics. Formal treatment studies are very much needed.     

Distinguishing bipolar and unipolar disorders: an isomer model

BACKGROUND: As division between unipolar and bipolar disorders can be problematic, we sought to develop a self-report questionnaire of mood 'highs' that would both distinguish true Bipolar Disorder from any elevated mood states in unipolar depression and sharpen the distinction between Bipolar I and II conditions. METHOD: A 46-item questionnaire was developed and completed by 157 out-patients presenting with a major depressive episode, and clinically diagnosed as having either Bipolar I (BP-I), Bipolar II (BP-II) or Unipolar (UP) depression, although DSM-IV duration criteria for BP-I and BP-II were not imposed. RESULTS: Factor analyses identified four key constructs to mood 'highs', while additional analyses refined the questionnaire to 27 items. The refined measure was highly accurate in distinguishing composite Bipolar (BP-I and BP-II) from UP subjects (AUC = 0.93, sensitivity = 81%; specificity = 98%, positive predictive value = 0.95). Questionnaire scores were similar for BP-I and BP-II subjects, raising the possibility that the core mood state differs little in severity across the two expressions, and that their distinction allows an alternative model that weights the presence or absence of psychotic features. CONCLUSIONS: Our study advances understanding of boundary distinctions between bipolar and unipolar mood disorders, and between BP-I and BP-II conditions, and allows consideration of a model distinguishing BP-I from BP-II by the presence of psychotic features only. The described model is the mirror image of a hierarchical structural model for conceptualizing psychotic and melancholic depression, allowing an 'isomer model' for linking the mood swing states.     

Validating affective temperaments in their subaffective and socially positive attributes: psychometric, clinical and familial data from a French national study

BACKGROUND: One of the major objectives of the French National EPIDEP Study was to show the feasibility of systematic assessment of bipolar II (BP-II) disorder and beyond. In this report we focus on the utility of the affective temperament scales (ATS) in delineating this spectrum in its clinical as well as socially desirable expressions. METHODS: Forty-two psychiatrists working in 15 sites in four regions of France made semi-structured diagnoses based on DSM IV criteria in a sample of 452 consecutive major depressive episode (MDE) patients (from which bipolar I had been removed). At least 1 month after entry into the study (when the acute depressive phase had abated), they assessed affective temperaments by using a French version of the precursor of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS). Principal component analyses (PCA) were conducted on hyperthymic (HYP-T), depressive (DEP-T) and cyclothymic (CYC-T) temperament subscales as assessed by clinicians, and on a self-rated cyclothymic temperament (CYC-TSR). Scores on each of the temperament subscales were compared in unipolar (UP) major depressive disorder versus BP-II patients, and in the entire sample subdivided on the basis of family history of bipolarity. RESULTS: PCAs showed the presence of a global major factor for each clinician-rated subscale with respective eigenvalues of the correlation matrices as follows: 7.1 for HYP-T, 6.0 for DEP-T, and 4.7 for CYC-T. Likewise, on the self-rated CYC-TSR, the PCA revealed one global factor (with an eigenvalue of 6.6). Each of these factors represented a melange of both affect-laden and adaptive traits. The scores obtained on clinician and self-ratings of CYC-T were highly correlated (r=0.71). The scores of HYP-T and CYC-T were significantly higher in the BP-II group, and DEP-T in the UP group (P<0.001). Finally, CYC-T scores were significantly higher in patients with a family history of bipolarity. CONCLUSION: These data uphold the validity of the affective temperaments under investigation in terms of face, construct, clinical and family history validity. Despite uniformity of depressive severity at entry into the EPIDEP study, significant differences on ATS assessment were observed between UP and BP-II patients in this large national cohort. Self-rating of cyclothymia proved reliable. Adding the affective temperaments-in particular, the cyclothymic-to conventional assessment methods of depression, a more enriched portrait of mood disorders emerges. More provocatively, our data reveal socially positive traits in clinically recovering patients with mood disorders.     

Psychosocial disability and work role function compared across the long-term course of bipolar I, bipolar II and unipolar major depressive disorders

OBJECTIVE: The research literature on psychosocial disability and work in mood disorders has either focused on relatively short-term course, or did not consider direct comparisons of these domains across all three of the affective subtypes of bipolar I (BP-I), bipolar II (BP-II), and unipolar major depressive disorders (UP-MDD). METHODS: Mean composite measures of psychosocial impairment and months at specific levels of overall and work impairment were compared for 158 BP-I, 133 BP-II, and 358 UP-MDD patients based on semi-structured interviews conducted during 15 years of follow-up in the NIMH Collaborative Depression Study (CDS). These are contrasted with a single month of psychosocial impairment ratings for a sample of 1787 subjects with no current psychiatric disorder. RESULTS: Patients with mood disorders experienced some degree of disability during the majority of long-term follow-up (54 to 59% of months), including 19 to 23% of months with moderate and 7 to 9% of months with severe overall impairment. Severe disability occurred a substantial percentage of time only in the specific area of work role function. BP-I patients were completely unable to carry out work role functions during 30% of assessed months, which was significantly more than for UP-MDD and BP-II patients (21% and 20%, respectively). CONCLUSIONS: These findings have public health, economic, and clinical importance, and underscore the need to reduce the chronicity and impairment associated with these three prevalent affective disorder subtypes. Interventional research is just beginning to address these challenges.     

A downscaled practical measure of mood lability as a screening tool for bipolar II

BACKGROUND: Current data indicate a strong association between Cyclothymic temperament (and its more ultradian counterpart of mood lability) and Bipolar II (BPII). Administration of elaborate measures of temperament are cumbersome in routine practice. Accordingly, the aim of the present analyses was to test if a practical measure of mood lability was unique to BPII, in comparison with major depressive disorder (MDD). METHODS: Using the Structured Clinical Interview for DSM-IV Axis I Disorders, Clinician Version as modified by us [J. Affect. Disord. 73 (2003) 33; Curr. Opin. Psychiatry 16 (2003) S71], we interviewed 62 consecutive BPII outpatients, as well as their 59 MDD counterparts during a major depressive episode (MDE). Hypomanic symptoms during MDE were systematically assessed: three or more such symptoms defined depressive mixed state (DMX3) on the basis of previous work by us [J. Affect. Disord. 73 (2003) 113]. A downscaled definition of trait mood lability was adapted from Akiskal et al. [Arch. Gen. Psychiatry 52 (1995) 114] and Angst et al. [J. Affect. Disord. 73 (2003) 133], requiring a positive response to one of two queries on whether one is a person with frequent "ups and downs" in mood, and whether such mood swings occur for no reason. The patients selected for inclusion had not received neuroleptics and antidepressants for at least 2 weeks prior to the index episode, they were free of substance and alcohol abuse, and did not meet the DSM-IV criteria for borderline personality disorder (BPD). Associations between mood swings and clinical variables were tested by logistic regression (STATA 7). RESULTS: Mood swings were endorsed by 50.4% of the entire sample: 62.9% of BPII and 37.2% of MDD (p = 0.0047). This practical measure of mood lability was significantly associated with BPII, lower age at onset, high depressive recurrences, atypical features, and DMX3. When controlled for number of major affective episodes, mood swings were still significantly associated with BP-II. Sensitivity and specificity of mood swings for predicting BPII were 62.9% and 62.7%, respectively. LIMITATION: The low specificity of trait mood lability for BPII diagnosis is probably due to the fact that we used a downscaled simplified measure of this trait. CONCLUSIONS: On the other hand, the relatively high sensitivity of our downscaled measure of mood lability for predicting BPII supports its usefulness as a screening tool for this diagnosis. The lack of association between self-reported mood lability and number of major mood episodes indicates that such lability does not reflect the perception of history of frequent episodes, and that it has some validity as a trait indicator. Given that our sample excluded patients meeting the DSM-IV criteria for BPD, contradicts the opinion of the latter manual that such mood lability represents its pathognomonic characteristic that distinguishes it from BPII. The bipolar nature of mood lability is further supported by significant associations with external validating criteria for bipolarity. Overall, these data indicate that in the differential diagnosis between MDD and BPII, trait mood lability favors the latter at a significant statistical level.     

Temperamental commonalities and differences in euthymic mood disorder patients, creative controls, and healthy controls

OBJECTIVE: Understanding of mood disorders can be enhanced through assessment of temperamental traits. We explored temperamental commonalities and differences among euthymic bipolar (BP) and unipolar (MDD) mood disorder patients, creative discipline graduate student controls (CC), and healthy controls (HC). METHODS: Forty-nine BP, 25 MDD, 32 CC, and 47 HC completed self-report temperament/personality measures including: The Affective Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS-A); the Revised NEO Personality Inventory (NEO-PI-R); and the Temperament and Character Inventory (TCI). RESULTS: Euthymic BP, MDD, and CC, compared to HC, had significantly increased cyclothymia, dysthymia and irritability scores on TEMPS-A; increased neuroticism and decreased conscientiousness on NEO-PI-R; and increased harm avoidance and novelty seeking as well as decreased self-directedness on TCI. TEMPS-A cyclothymia scores were significantly higher in BP than in MDD. NEO-PI-R openness was increased in BP and CC, compared to HC, and in CC compared to MDD. TCI self-transcendence scores in BP were significantly higher than in MDD, CC, and HC. LIMITATIONS: Most of the subjects were not professional artists, and represented many fields; temperament might be different in different art fields. CONCLUSIONS: Euthymic BP, MDD, and CC compared to HC, had prominent temperamental commonalities. However, BP and CC had the additional commonality of increased openness compared to HC. BP had particularly high Cyclothymia scores that were significantly higher then those of MDD. The prominent BP-CC overlap suggests underlying neurobiological commonalities between people with mood disorders and individuals involved in creative disciplines, consistent with the notion of a temperamental contribution to enhanced creativity in individuals with bipolar disorders.     

Toward a definition of a cyclothymic behavioral endophenotype: which traits tap the familial diathesis for bipolar II disorder?

BACKGROUND: Although the cyclothymic temperament appears to be related to the familial diathesis of bipolar disorder, exhibiting high sensitivity for bipolar II (BP-II) disorder, it is presently uncertain which of its constituent traits are specific for this disorder. METHODS: In a sample of 446 major depressive patients (BP-II and unipolar), in the French National EPIDEP study, the cyclothymic temperament was assessed by using clinician- and self-rated scales. We computed the frequency of individual traits and relative risk for family history of bipolarity. RESULTS: From both clinician- and self-rated scales, four items related to mood reactivity, energy, psychomotor and mental activity were significantly highly represented in the subgroup with positive family history of bipolarity. The item "rapid shifts in mood and energy" obtained the highest relative risk (OR=3.42) for positive family history of bipolarity. CONCLUSION: These findings delineate those cyclothymic traits which are most likely to tap a familial-genetic diathesis for BP-II, thereby identifying traits which can best serve as a behavioral endophenotype for this bipolar subtype. Such an endophenotype might underlie the cyclic course of bipolar disorder first described in France 150 years ago by Falret and Baillarger.     

Is there a continuity between bipolar and depressive disorders?

BACKGROUND: Recent studies questioned the current categorical split of mood disorders into bipolar disorders (BP) and depressive disorders (MDD). METHODS: Medline database search of papers from the last 10 years on the categorical-dimensional classification of mood disorders. Various combinations of the following key words were used: mood disorders, bipolar, unipolar, major depressive disorder, spectrum, category/categorical, classification, continuity. Only English language clinical papers were included, review papers were excluded, similar papers selected by quality. The number of papers found was 1,141. The number of papers selected was 109. RESULTS: The continuity/spectrum between BP (mainly BP-II) and MDD was supported by the following findings:(1) high frequency of mixed states (mixed mania, mixed hypomania, mixed depression, i.e. co-occurring depression and noneuphoric manic/hypomanic symptoms) because opposite polarity symptoms in the same episode do not support a hypomania/mania-depression splitting; (2) MDD was the most common mood disorder in BP probands' relatives; (3) no bimodal distribution of distinguishing symptoms between BP and MDD; (4) bipolar signs not uncommon in MDD; (5) many MDD shifting to BP; (6) many lifetime manic/hypomanic symptoms in MDD; (7) correlation between lifetime manic/hypomanic symptoms and MDD symptoms; (8) hypomania factors in MDD; (9) MDD often recurrent; (10) similar cognitive style.The categorical distinction between BP (mainly BP-I) and MDD was supported by the following findings: (1) BP more common in BP probands' relatives; (2) lower age at BP onset; (3) females as common as males in BP-I, more common than males in MDD; (4) BP-I depression more atypical and retarded, MDD depression more sleepless and agitated; (5) BP more recurrent. CONCLUSIONS: Focusing on mood spectrum's extremes (BP-I vs. MDD), a categorical distinction seems supported. Focusing on midway disorders (BP-II and MDD plus bipolar signs), a continuity/spectrum seems supported. Results seem to support both a categorical and a dimensional view of mood disorders.     

Bipolar or unipolar? - the question for clinicians and researchers

BACKGROUND: Correct diagnosis and criteria of affective disorders is always a subject of interest to researchers and practitioners. METHODS: The study aimed at assessing frequency of various traits and symptoms of bipolar affective disorders (BP-I, BP-II, BP-S spectrum) in patients (n=246) treated for recurrent affective disorders (unipolar-UP). The analysis was based on criteria of affective disorders of Ghaemi et al. and Hirschfeld's Mood Disorders Questionnaire. RESULTS: UP was confirmed in 32.9% of individuals, whereas 19.5% were BP-I, 35% BP-II and 12.6% BP-S. UP patients were significantly more often professionally active than those with BP (37.2% vs. 22.7%). Duration of a disorder was significantly shorter and the number of depressive episodes lower in the UP group. In comparison with UP, BP-I were associated with the previous occurrence of unusual and/or risky behaviour (OR=24.5), excessive, irrational expenditure (OR=21.1), lack of a critical attitude with respect to social behaviour (OR=20.3), increased sex drive (OR=17.7), and excessive self-confidence (OR=12). BP-II were associated with a lack of criticism with regard to social behaviour (OR=12.7) and unusual and/or risky behaviour (OR=10). Spectrum BP were most strongly associated with short term hypomanic episodes, including drug induced episodes (OR=15.8) and lack of criticism (OR=11.8). Early onset of depression (before 25 years of age) increased the risk of all three types of BP (by a factor of 3 to 5). LIMITATIONS: This was a naturalistic study, in which treatment was uncontrolled. CONCLUSIONS: Results of the study are a voice in the discussion on too narrow criteria defining bipolar affective disorders.     

Validating the bipolar spectrum in the French National EPIDEP Study: overview of the phenomenology and relative prevalence of its clinical prototypes

BACKGROUND: Few studies have been undertaken to ascertain the feasibility of using the bipolar (BP) spectrum in clinical practice. The only systematic national study is the French EPIDEP Study of consecutive inpatients and outpatients presenting with major depressive episodes (MDE). The protocol was developed in 1994 and implemented in 1995; publication of its first data began in 1998. This report provides the complete data set of the EPIDEP. METHODS: Forty-eight psychiatrists, practicing in 15 sites in four regions of France (Paris, Besan?on, Bordeaux and Marseille), were all trained on a common protocol based on DSM-IV criteria for MDE (n=537) subdivided into BP-I (history of mania), BP-II (history of hypomania), as well as extended definitions of the "softer spectrum" beyond BP-I and BP-II. Measures tapping into this spectrum included the Hypomania Checklist (HCA), the cyclothymic (CT), depressive (DT) and hyperthymic (HT) temperament scales. These measures and course permitted post-hoc assignment of MDE in the bipolar spectrum, based in part on the Akiskal, H.S., Pinto, O., 1999. [The evolving bipolar spectrum: Prototypes I, II, III, IV. Psychiatr. Clin. North Am. 22, 517-534] proposal: depression with history of spontaneous hypomanic episodes (DSM-IV, BP-II), cyclothymic depressions (BP-II(1/2)), antidepressant-associated hypomania (BP-III) and hyperthymic depressions (BP-IV). was thereby limited to an exclusion diagnosis for the remainder of MDE. LIMITATION: In the clinical setting, psychiatrists cannot be entirely blind to the observations in the various clinical evaluations and instruments. However, the systematic multisite collection of such data tended to minimize any such biases. RESULTS: After excluding patients lost to follow-up, among 493 presenting with MDE with complete data files, the BP-II rate was estimated at index at 20%; 1 month later, systematic probing for hypomania doubled the rate of BP-II to 39%. The comparison between BP-II and UP showed differential phenomenology, such as hypersomnia, increased psychomotor activation, guilt feelings and suicidal thoughts in BP-II. Related data demonstrated the importance of CT in further qualifying of MDE to define a distinct, more severe ("darker") BP-II(1/2) variant of BP-II. Moreover, BP-III, arising from DT and associated with antidepressants, emerged as a valid soft bipolar variant on the basis of the phenomenology of hypomania and bipolar family history. Finally, we found preliminary evidence for the inclusion of BP-IV into the bipolar spectrum, its total hypomania score falling intermediate between BP-II and strict UP. Using this broader diagnostic framework, the bipolar spectrum (the combined "hard" BP-I phenotype, BP-II and the soft spectrum) accounted for 65% of MDE. CONCLUSION: The EPIDEP study achieved its objectives by demonstrating the feasibility of identifying the bipolar spectrum at a national level, and refining its phenomenology through rigorous clinical characterization and validation of bipolar spectrum subtypes, including MDE with brief hypomanias, cyclothymia and hyperthymia. The spectrum accounted for two out of three MDE, making "strict UP" less prevalent than BP as redefined herein. Our findings were anticipated by Falret, who in 1854 had predicted that many melancholic patients in the community would 1 day be classified in his circular group. We also confirmed Baillarger's observation in the same year that episodes (in this study, hypomanic episodes) could last as short as 2 days. Our findings deriving from a systematic French national database a century and a half later invite major shifts in clinical and public health services, as well as in the future conduct of psychopharmacologic trials. In this respect, the systematic training of clinicians in four regions of France represents a national resource for affective disorders and can serve as a model to effect change in diagnostic practice in other countries.     

Bipolar II vs. unipolar depression: psychopathologic differentiation by dimensional measures

BACKGROUND: Clinical presentations of depression in bipolar disorder are varied, inconsistent and often confusing. Most previous studies have focused on bipolar I (BP-I). Given that bipolar II (BP-II) is the more common bipolar phenotype, which is often confused with unipolar (UP), the aim of the current analyses is to delineate the symptomalogic differences between BP II vs. UP MDD in a large national sample. METHODS: The data derived from the French National EPIDEP study (n = 452 DSM-IV major depressives), subdivided into BP-II (n = 196) and UP (n = 256). The BP II group included major depressives with both spontaneous and antidepressant-associated hypomania based on our finding of similarity in rates of familial bipolarity in the two subgroups. At index presentation, depression was assessed by the clinician (using HAM-D and the Rosenthal Atypical Depression Scale) and by the patient (using the Multi-Visual Analog Scale of Bipolarity, MVAS-BP). Principal component analyses (PCA with varimax rotation) were conducted on HAM-D and MVAS-BP in the total population and separately in BP-II and UP. We performed inter-group comparative tests (UP vs. BP-II) on factorial scores derived from PCAs and correlation tests between these factorial scores. RESULTS: The PCA on "HAM-D + Rosenthal scale" showed the presence of nine major factors: F1-2 "weight changes", F3-4 "sleep disturbances", F5 "sadness-guilt", F6 "retardation-fatigue", F7 "somatic", F8 "diurnal variation" and F9 "insight-delusion". The PCA on MVAS-BP revealed the presence of eight principal components: F1 "psychomotor retardation", F2 "central pain", F3 "somatic", F4 "social contact", F5 "worry", F6 "loss of interest", F7 "guilt" and F8 "anger". Despite uniformity in global intensity of depression, significant differences were observed as follows: higher score on "psychomotor retardation" (p = 0.03), "loss of interest" (p = 0.057) and "insomnia" (p = 0.05) in the UP group, and higher score on "hypersomnia" (p = 0.008) in the BP-II group. Correlation analyses between clinician- and self-rating revealed the presence of higher number of significant coefficients in the UP vs. BP-II group (p < or =0.001). LIMITATION: A three-way comparison between BP-I, BP-II and UP may have yielded somewhat different results. CONCLUSION: Our data indicate greater psychomotor retardation, stability and uniformity in the clinical picture of strictly defined UP depression. By contrast, bipolar II depression appeared to be characterized, despite the hypersomnic tendency, by psychomotor activation. This would indicate greater mixed features than those observed in UP. Moreover, in BP-II, there was less agreement between clinician vs. self-rating on the presence of various features of depression. Taken together, these findings explain why BP-II depression is missed by clinicians as a genuine depression.     

Neuroprotective and neurogenesis agent for treating bipolar II disorder: add-on memantine to mood stabilizer works

Bipolar disorder, characterized by a dysregulation of mood, impulsivity, risky behavior and interpersonal problems, is a recurrent and often becomes chronic psychiatric illness. However, bipolar subtypes are not often recognized in psychiatric settings, especially bipolar II subtype, until Akiskal and Angst made clear definition to bipolar I (BP-I) and bipolar II (BP-II) disorder in 1999. More and more studies, not only on family inheritance, diagnosis, but also on disease process have been reported that BP-I and BP-II are two different disorders with distinct pathological mechanisms. In general, patients with BP-II express less symptoms and have shorter hypomania stages than BP-I. According to a longitudinal research, patients with BP-II have poor recovery than do BP-I patients. Memantine used to be recognized as a noncompetitive N-methyl-d-aspartate receptor antagonist. However, it was found to have neuroprotective and neurogenesis effect in several neurodegenerative diseases in the past years. We found that memantine could inhibit brain inflammatory response through its action on neuroglial cells and provide neurotrophic effect. The above evidences of benefit on auto-immune system with memantine would support that memantine as add-on therapy to valproate might be more effective than valproate alone on improvement of the neuron degeneration in bipolar disorders. Review articles indicate that not only the mood stabilizers provide with good neuroprotection, but the memantine also have conspicuous anti-autoimmune and neurogenesis effect. Therefore, we propose that drugs with neuroprotective effect and neurotrophic effect may treat neurodegenerative diseases including BP-II. The combination treatment of mood stabilizers memantine may not only augment and improve the remedy for bipolar disorders, but also repair the damaged neurons and neurogenesis through activation of astroglial cell and release of neurotrophic factors.     

Bipolar II with and without cyclothymic temperament: "dark" and "sunny" expressions of soft bipolarity

BACKGROUND: In the present report deriving from the French national multi-site EPIDEP study, we focus on the characteristics of Bipolar II (BP-II), divided on the basis of cyclothymic temperament (CT). In our companion article (Hantouche et al., this issue), we found that this temperament in its self-rated version correlated significantly with hypomanic behavior of a risk-taking nature. Our aim in the present analyses is to further test the hypothesis that such patients-assigned to CT on the basis of clinical interview-represent a more "unstable" variant of BP-II. METHODS: From a total major depressive population of 537 psychiatric patients, 493 were re-examined on average a month later; after excluding 256 DSM-IV MDD and 41 with history of mania, the remaining 196 were placed in the BP-II spectrum. As mounting international evidence indicates that hypomania associated with antidepressants belongs to this spectrum, such association per se did not constitute a ground for exclusion. CT was assessed by clinicians using a semi-structured interview based on in its French version; as two files did not contain full interview data on CT, the critical clinical variable in the present analyses, this left us with an analysis sample of 194 BP-II. Socio-demographic, psychometric, clinical, familial and historical parameters were compared between BP-II subdivided by CT. Psychometric measures included self-rated CT and hypomania scales, as well as Hamilton and Rosenthal scales for depression. RESULTS: BP-II cases categorically assigned to CT (n=74) versus those without CT (n=120), were differentiated as follows: (1). younger age at onset (P=0.005) and age at seeking help (P=0.05); (2). higher scores on HAM-D (P=0.03) and Rosenthal (atypical depressive) scale (P=0.007); (3). longer delay between onset of illness and recognition of bipolarity (P=0.0002); (4). higher rate of psychiatric comorbidity (P=0.04); (5). different profiles on axis II (i.e., more histrionic, passive-aggressive and less obsessive-compulsive personality disorders). Family history for depressive and bipolar disorders did not significantly distinguish the two groups; however, chronic affective syndromes were significantly higher in BP-II with CT. Finally, cyclothymic BP-II scored significantly much higher on irritable-risk-taking than "classic" driven-euphoric items of hypomania. CONCLUSION: Depressions arising from a cyclothymic temperament-even when meeting full criteria for hypomania-are likely to be misdiagnosed as personality disorders. Their high familial load for affective disorders (including that for bipolar disorder) validate the bipolar nature of these "cyclothymic depressions." Our data support their inclusion as a more "unstable" variant of BP-II, which we have elsewhere termed "BP-II 1/2." These patients can best be characterized as the "darker" expression of the more prototypical "sunny" BP-II phenotype. Coupled with the data from our companion paper (Hantouche et al., 2003, this issue), the present findings indicate that screening for cyclothymia in major depressive patients represents a viable approach for detecting a bipolar subtype that could otherwise be mistaken for an erratic personality disorder. Overall, our findings support recent international consensus in favoring the diagnosis of cyclothymic and bipolar II disorders over erratic and borderline personality disorders when criteria for both sets of disorders are concurrently met.     

The comparative clinical phenotype and long term longitudinal episode course of bipolar I and II: a clinical spectrum or distinct disorders?

BACKGROUND: The present analyses were designed to compare the clinical characteristics and long-term episode course of Bipolar-I and Bipolar-II patients in order to help clarify the relationship between these disorders and to test the bipolar spectrum hypothesis. METHODS: The patient sample consisted of 135 definite RDC Bipolar-I (BP-I) and 71 definite RDC Bipolar-II patients who entered the NIMH Collaborative Depression Study (CDS) between 1978 and 1981; and were followed systematically for up to 20 years. Groups were compared on demographic and clinical characteristics at intake, and lifetime comorbidity of anxiety and substance use disorders. Subsets of patients were compared on the number and type of affective episodes and the duration of inter-episode well intervals observed during a 10-year period following their resolution of the intake affective episode. RESULTS: BP-I and BP-II had similar demographic characteristics and ages of onset of their first affective episode. Both disorders had more lifetime comorbid substance abuse disorders than the general population. BP-II had a significantly higher lifetime prevalence of anxiety disorders in general, and social and simple phobias in particular, compared to BP-I. Intake episodes of BP-I were significantly more acutely severe. BP-II patietns had a substantially more chronic course, with significantly more major and minor depressive episodes and shorter inter-episode well intervals. BP-II patients were prescribed somatic treatment a substantially lower percentage of time during and between affective episodes. LIMITATIONS: BP-I patients with severe manic course are less likely to be retained in long-term follow-up, whereas the reverse might be true for BP-II patients who are significantly more prone to depression (i.e., patients with less inclination to depression and with good prognosis may have dropped out in greater proportions); this could increase the gap in long term course characteristics between the two samples. The greater chronicity of BP-II may be due, in part, to the fact that the patients were prescribed somatic treatments substantially less often both during and between affective episodes. CONCLUSIONS: The variety in severity of the affective episodes shows that bipolar disorders, similar to unipolar disorders, are expressed longitudinally during their course as a dimensional illness. The similarities of the clinical phenotypes of BP-I and BP-II, suggest that BP-I and BP-II are likely to exist in a disease spectrum. They are, however, sufficiently distinct in terms of long-term course (i.e., BP-I with more severe episodes, and BP-II more chronic with a predominantly depressive course), that they are best classified as two separate subtypes in the official classification systems.     

The use of the GBI as predictor of bipolar disorder in a population of adolescent offspring of parents with a bipolar disorder

OBJECTIVE: To assess the usefulness of the General Behavior Inventory (GBI) to predict the development of mood disorders in the offspring of parents with bipolar disorder. METHOD: The GBI and the K-SADS (first measurement) and the SCID (last measurement) were used to assess psychopathology among 129 adolescent and young adult offspring of a bipolar parent with an interval of 5 years. Based on the SCID results at the last measurement, the offspring were assigned to one of four groups: with bipolar mood disorder, with unipolar mood disorders, with non-mood disorders and without disorders and GBI-scores at the first measurement were compared across the four groups. RESULTS: The scores on the Depression scale of the GBI for the offspring who later developed a bipolar or any mood disorder were significantly higher than for the offspring who did not develop a mood disorder across a 5-year interval. For the offspring with a unipolar mood disorder at the first measurement, the scores on the Depression scale were significantly higher for those who switched to bipolar disorder versus those who remained unipolar. CONCLUSIONS: The GBI can be used in a high-risk sample of offspring of parents with bipolar disorder as a self-report measure as an aid to detect those who will develop bipolar disorder across a 5-year interval.     

Atypical depression: a variant of bipolar II or a bridge between unipolar and bipolar II?

BACKGROUND: Although increasing data link atypical depression (AD) to the bipolar spectrum, controversies abound about the extent of the overlap. In particular, the Columbia group, which has pioneered in providing data on operational clarity and pharmacological specificity of atypical depressions, has nonetheless consistently avoided studying its discriminatory validity from bipolar II (BP-II). Accordingly, we undertook a full scale validation of such a link in a large clinical sample of BP-II and unipolar (UP) major depressive disorder (MDD). METHODS: Consecutive 348 BP-II and 254 MDD outpatients presenting with major depressive episodes (MDE) were interviewed off psychoactive drugs with a modified Structured Clinical Interview for DSM-IV, the structured Family History Screen and the Hypomania Interview Guide. We used the DSM-IV criteria for "atypical features" specifier. Depressive mixed state was defined as > or =3 concurrent hypomanic signs and symptoms during MDE. Bipolar validators were age at onset, high depressive recurrence, depressive mixed state and bipolar family history (types I and II). Univariate and multivariate logistic regression were used to examine associations and control for confounding variables. RESULTS: Frequency of AD was 43.0% in the combined BP-II and MDD sample. AD, versus non-AD, had significantly higher rates of BP-II. AD was significantly associated with all bipolar validators, among which family history was the most robust. A dose-response relationship was found between number of atypical symptoms during MDE and bipolar family history loading. The association between bipolar family history and number of atypical symptoms remained significant after controlling for the confounding effect of BP-II. Bipolar family history was strongly associated with the atypical symptoms of leaden paralysis and hypersomnia. CONCLUSION: These results confirm a strong link between AD and bipolar validators along psychopathologic and familial grounds. From a practical standpoint, AD is best viewed as a variant of BP-II. Clinicians confronted with MDE patients presenting with atypical features should strongly consider a BP-II diagnosis. In a more hypothetical vein, atypicality-or some associated features thereof-might serve as a nosologic bridge between UP and BP-II.     

The role of cyclothymia in atypical depression: toward a data-based reconceptualization of the borderline-bipolar II connection

OBJECTIVE: Recent data, including our own, indicate significant overlap between atypical depression and bipolar II. Furthermore, the affective fluctuations of patients with these disorders are difficult to separate, on clinical grounds, from cyclothymic temperamental and borderline personality disorders. The present analyses are part of an ongoing Pisa-San Diego investigation to examine whether interpersonal sensitivity, mood reactivity and cyclothymic mood swings constitute a common diathesis underlying the atypical depression-bipolar II-borderline personality constructs. METHOD: We examined in a semi-structured format 107 consecutive patients who met criteria for major depressive episode with DSM-IV atypical features. Patients were further evaluated on the basis of the Atypical Depression Diagnostic Scale (ADDS), the Hopkins Symptoms Check-list (HSCL-90), and the Hamilton Rating Scale for Depression (HRSD), coupled with its modified form for reverse vegetative features as well as Axis I and SCID-II evaluated Axis II comorbidity, and cyclothymic dispositions ('APA Review', American Psychiatric Press, Washington DC, 1992). RESULTS: Seventy-eight percent of atypical depressives met criteria for bipolar spectrum-principally bipolar II-disorder. Forty-five patients who met the criteria for cyclothymic temperament, compared with the 62 who did not, were indistinguishable on demographic, familial and clinical features, but were significantly higher in lifetime comorbidity for panic disorder with agoraphobia, alcohol abuse, bulimia nervosa, as well as borderline and dependent personality disorders. Cyclothymic atypical depressives also scored higher on the ADDS items of maximum reactivity of mood, interpersonal sensitivity, functional impairment, avoidance of relationships, other rejection avoidance, and on the interpersonal sensitivity, phobic anxiety, paranoid ideation and psychoticism of the HSCL-90 factors. The total number of cyclothymic traits was significantly correlated with 'maximum' reactivity of mood and interpersonal sensitivity. A significant correlation was also found between interpersonal sensitivity and 'usual' and 'maximum' reactivity of mood. LIMITATION: Correlational study. CONCLUSIONS: Mood lability and interpersonal sensitivity traits appear to be related by a cyclothymic temperamental diathesis which, in turn, appears to underlie the complex pattern of anxiety, mood and impulsive disorders which atypical depressive, bipolar II and borderline patients display clinically. We submit that conceptualizing these constructs as being related will make patients in this realm more accessible to pharmacological and psychological interventions geared to their common temperamental attributes. More generally, we submit that the construct of borderline personality disorder is better covered by more conventional diagnostic entities.